Randomized Trial of SGLT2 Inhibitor Identifies Target Proteins in Diabetic Kidney Disease

Abstract

IntroductionSodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as novel therapeutics to treat diabetic kidney disease (DKD). Albeit the beneficial effects of SGLT2i have been demonstrated, their target mechanisms on kidney function are unknown. The current study aimed to elucidate these mechanisms by studying SGLT2i-induced changes in the urinary proteome of persons with type 2 diabetes (T2D) and DKD. Methods40 T2D participants were enrolled in a double blind randomized cross-over trial at the Steno Diabetes Center Copenhagen, Denmark. They were treated with 10 mg of dapagliflozin for 12 weeks. 32 participants with complete urinary proteomics measures before and after the trial were included. All participants received RAS blockade and had albuminuria, (UACR ≥ 30 mg/g). A type 1 diabetes cohort consisting healthy controls and persons with DKD was included for validation. Urinary proteome changes were analyzed using Wilcoxon signed-rank test. Functional enrichment analysis was conducted to discover affected biological processes. ResultsDapagliflozin treatment significantly (Padjusted < 0.05) affected 36 urinary peptide fragments derived from 19 proteins. 18 proteins were correspondingly reflected in the validation cohort. A multi-fold change in peptide abundance was observed in many proteins (A1BG, ALB, CALD1, COLCRNN, HSP90AB1, IGLL5, PI16, PTGDS, SERPINA1). These also included urinary biomarkers of kidney fibrosis and function (type I & III collagens and albumin). Biological processes relating inflammation, wound healing, and kidney fibrosis were enriched. ConclusionThe current study discovers the urinary proteome impacted by the SGLT2i providing new potential target sites and pathways especially relating to wound healing and inflammation.